Reprogramming the pancreatic tumor microenvironment with immunotherapy

 描述(申请人提供)：癌症免疫治疗是过去十年中最大的突破之一。然而，到目前为止，单剂免疫治疗的成功仅限于少数实体恶性肿瘤，包括黑色素瘤、肾细胞癌和非小细胞肺癌。对检查点抑制剂有反应的癌症和像胰腺导管腺癌(PDA)这样没有反应的癌症之间的一个区别是肿瘤微环境(TME)的免疫状态。与许多其他实体恶性肿瘤一样，动脉导管未闭被认为是“非免疫原性的”。我们最近报道，在单剂新辅助剂量的粒细胞-巨噬细胞集落刺激因子(GM-CSF)分泌的PDA疫苗(GVAX)诱导形成新的具有免疫活性的第三级淋巴集合体，即有组织的淋巴结样结构后，PDA肿瘤仅在两周内就被切除，这是在未接种疫苗的患者切除的肿瘤组织中没有观察到的。这项先前的研究首次表明，基于疫苗的免疫疗法可以将免疫静止的TME重新编程为免疫活性的TME。然而，PDA TME中激活的T细胞分泌干扰素-γ，进而上调PD-1/PD-L1。因此，我们假设GVAX的治疗为抗PD-1/PD-L1靶向治疗的PDA TME提供了基础。为了支持这一假设，我们的临床前研究表明，将抗PD-1或PD-L1抗体与疫苗结合起来，可以提高效应T细胞渗入PDA的频率和PDA荷瘤小鼠的治愈率。为了进一步验证这一假设，我们将50名可切除PDA的患者登记并随机参加一项双臂临床试验，在手术切除他们的PDA前两周，接受GVAX加环磷酰胺(Cy)或联合抗PD-1抗体(Nivolumab)的一种新辅助治疗，然后再接受五种辅助免疫治疗。我们将比较治疗前核心活检和手术切除的肿瘤的PDA样本，并评估这项临床试验的主要终点(疫苗诱导的淋巴聚集中IL17A的表达)和次要终点(安全性、无病生存率和总生存率)。我们 将评估抗PD-1抗体联合Cy/GVAX对PD-L1/PD-1相关通路、疫苗诱导的免疫调节特征以及外周和肿瘤内抗原特异性T细胞反应的影响。这些结果有望确定PD-1/PD-L1途径在PDA TME中的调节作用，确定可能补偿PD-1阻断的替代调节途径，并确定PDA TME内的免疫反应特征。如果联合治疗组表现出淋巴聚集中IL17A表达增强和/或存活率高于Cy/GVAX单独使用，我们将在一项随机研究中将这两组治疗组与标准护理进行比较，样本量足以估计临床疗效的改善。

 DESCRIPTION (provided by applicant): Cancer immunotherapy is among the biggest breakthroughs in the last decade. However, the success of single agent immunotherapy has so far been limited to a few solid malignancies, including melanoma, renal cell carcinoma, and non-small cell lung cancer. One difference between cancers that have responded to checkpoint inhibitors and cancers like pancreatic ductal adenocarcinoma (PDA) that have not is the immune status of the tumor microenvironment (TME). PDA, like many other solid malignancies, was considered to be "non-immunogenic". We recently reported that PDA tumors resected just two weeks following a single neoadjuvant dose of a granulocyte-macrophage colony stimulating factor (GM-CSF) secreting PDA vaccine (GVAX) induces the formation of novel immunologically active tertiary lymphoid aggregates, organized lymph node-like structures that are not observed in tumor tissue resected from unvaccinated patients. This prior study showed for the first time that a vaccine-based immunotherapy can reprogram an immunologically quiescent TME into an immunologically active TME. However, activated T cells in the PDA TME secrete interferon-γ, which in turn upregulates PD-1/PD-L1. Thus, we hypothesize that treatment with GVAX primes the PDA TME for anti-PD-1/PD-L1-targeted therapy. Supporting this hypothesis, our preclinical studies showed that combining anti-PD-1 or PD-L1 antibodies with vaccines enhances the frequency of effector T cells infiltrating PDAs and the cure rate in PDA tumor-bearing mice. To further test this hypothesis, we will enroll and randomize 50 patients with resectable PDAs to a 2-arm clinical trial to receive either one neoadjuvant treatment with GVAX plus Cytoxan (Cy) alone or in combination with an anti-PD-1 antibody (nivolumab) two weeks prior to surgical resection of their PDAs, followed by five additional adjuvant immunotherapies. We will compare PDA specimens from a pre-treatment core biopsy and the surgically resected tumors and evaluate primary endpoint (IL17A expression in vaccine-induced lymphoid aggregates) and secondary endpoints (safety, disease free survival and overall survival) of this clinical trial. We will assess the effects of anti-PD-1 antibody blockade in combination with Cy/GVAX on the PD-L1/PD-1 associated pathways, vaccine-induced immune regulatory signatures, and peripheral and intratumoral antigen specific T cell responses. The results are expected to determine the role of modulating the PD-1/PD-L1 pathway in the PDA TME, to identify alternate regulatory pathways that may compensate for PD-1 blockade, and to identify signatures of immune response within the PDA TME. If the combinatorial treatment arm demonstrates enhanced IL17A expression in lymphoid aggregates and/or better survival than Cy/GVAX alone, we will compare the two treatment arms against standard of care in a randomized study with a sample size adequate to estimate an improvement in clinical efficacy.